The members of the low density lipoprotein (LDL) receptor gene family bind a broad spectrum of extracellular ligands. Traditionally, they had been regarded as mere cargo receptors that promote the endocytosis and lysosomal delivery of these ligands. However, recent genetic experiments have revealed critical functions for LDL receptor family members in the transmission of extracellular signals and the activation of intracellular tyrosine kinases. This process regulates neuronal migration and is crucial for brain development. Signaling through these receptors has been reported to require the interaction of their cytoplasmic tails with a number of intracellular adaptor proteins, including Disabled-1 (Dab1) and FE65. See copending U.S. Ser. No. 09/562,737.
We have now discovered that members of the LDL receptor gene family undergo endoproteolytic processing events that result in the release of their cytoplasmic tails into the cytoplasm. The present invention exploits this mechanism in novel methods and compositions for detecting proteolysis of LDL receptor transmembrane domains and resultant release of C-terminal tail domains.
Relevant Literature
Quinn et al. 1999, Exp Cell Res 251, 433–41; Grimsley et al., 1999, Thromb Res 94, 153–64; Herz, 2001, Neuron 29, 571–81; Van Uden et al. 1999, Mol Cell Neurosci 14, 129–140.